Early life adversity ablates sex differences in active versus passive threat responding in mice

Abstract

Early life adversity (ELA) heightens the risk for anxiety disorders (which are characterized by heightened fear and avoidance behaviors), with females being twice as likely as males to develop pathology. Pavlovian fear conditioning tasks have been used to study possible mechanisms supporting endophenotypes of pathology. Identification of sex and ELA selective effects on the nature of behavioral responding in these paradigms may provide a unique window into coping strategies in response to learned fear to guide more mechanistic studies. The goals of this study were two-fold; First, to test if male and female mice employed different coping strategies in response to threat learning using different conditioning parameters (low, medium, and high intensity foot shocks). Second, to test if ELA in the form of limited bedding and nesting (LBN) altered the behavioral response of mice to conditioning. Mice received 6 tone/foot-shock pairings at one of three different foot-shock intensities (0.35 mA; 0.57 mA; 0.7 mA). Freezing, darting, and foot-shock reactivity were measured across trials. During conditioning, control-reared female mice exhibited significantly higher rates of darting behavior compared to control males at nearly all shock intensities tested. LBN rearing decreased the proportion of darting females to levels observed in males. Thus, ELA in the form of LBN significantly diminished the recruitment of active versus passive coping strategies in female mice but did not generally change male responding. Additional work will be required to understand the neural basis of these behavioral effects. Findings extending from this work have the potential to shed light on how ELA impacts trajectories of regional brain development with implications for sex-selective risk for behavioral endophenotypes associated with pathology and possibly symptom presentation.

Keywords:

• Stress
• fear conditioning
• darting
• sex differences
• early life adversity

Acknowledgements

Authors would like to thank members of the Bath Lab for their comments on the figures and manuscript. Very special thanks to Kathleen Huntzicker for her comments, edits, and work on the manuscript. Thanks to Roberto Aponte Rivera for comments on the manuscript. We would also like to thank Jose Colom Lapetina for helping verify some of the darting videos and providing a second opinion on what constituted darting. This work was funded by the National Institutes of Health (NIMH- R01-MH115049- KGB; R01-MH115914-KGB and K00-MH123183- GMN)

Author contributions

GMN designed experiments. GMN conducted experiments. GMN and MB sorted and analyzed the data. GMN and KGB wrote the manuscript, with edits provided by MB.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Additional information

Notes on contributors

Gabriela Manzano Nieves

Gabriela Manzano Nieves is a Postdoctoral Fellow at Weill Cornell Medicine, New York, USA. Her work spans developmental and behavioral neuroscience, focusing on how changes in neuronal computations across a lifespan can bias behavior.

Marilyn Bravo

Marilyn Bravo is a medical student at the David Geffen School of Medicine in the UCLA/Charles R. Drew University of Medicine Medical Education Program. She graduated with Honors from Brown University in 2018 with a Sc.B in Neuroscience. Her research interests lie in neural development and mood disorders.

Kevin G. Bath

Dr. Kevin G. Bath is an Associate Professor of Medical Psychology in Psychiatry at Columbia University Medical Center, Research Scientist VI at New York State Psychiatric Institute (NYSP I), and Director of the Rodent Behavioral Core facility at NYSP I. His research interests include the impact of early life adversity on neurobehavioral development, sex differences in response to adversity, and evolutionary biology.